Abstract 3940: Novel Bax activators for targeted breast cancer therapy
Authors: Doerte Raphaela Fricke, Gang Liu, Hyejin Kim, Pingyuan Wang, Xi Liu, Haiying Chen, Ruixia Ma, Junhai Xu, Jia Zhou, Qiang Shen
Journal: Cancer Research (2022)

Abstract Breast cancer is one of the leading causes of cancer-related deaths in American women and the most common cancer in women with more than 280,000 estimated new cases in 2021 in the US. Therefore, there is an urgent need of advanced treatment regimens. Particularly the subgroups of estrogen receptor (ER)-negative breast cancers (ENBC) and the even worse triple-negative breast cancer (TNBC), a subtype of ENBC with a high metastatic potential, are lacking efficient treatment methods. Thus, developing more effective drugs for ENBC/TNCB treatment remains an unmet medical need. The pro-apoptotic protein Bax in active form was shown to be downregulated in most cancers. As a result, the balance between Bax and its antagonist Bcl-2 gets disturbed, thereby leading to dysfunctional apoptotic signaling in favor of cancer cell survival. Hence, drug discovery for Bax activation is a promising approach for developing novel cancer therapies. The small molecules GL0385 and GL0388 were identified from our progenitor molecules including small-molecule Bax activator (SMBA1), CYD-2-11, and CYD-4-61. The CYD compounds specifically target the Ser184 residue of Bax and have shown apoptosis-inducing effects in vitro and in vivo. These lead Bax activators provided proof-of-concept studies while further optimization is imperative to mitigate potential toxicity, leading to the discovery of advanced lead molecules GL0385 and GL0388. Treatment with either GL0385 or GL0388 resulted in significantly decreased cell proliferation in MDA-MB-231, MDA-MB-468, BT549, MDA-MB-453, MCF-7, and MDA-MB-361 cells. Additionally, MDA-MB-231 cells treated with GL0385 or GL0388 showed reduced migration and invasion, compared to control cells. Western blot analysis confirmed increased protein levels of Bax, cleaved PARP, cleaved caspase 3, and cytochrome C. These results demonstrate that GL0385 and GL388 have a significant impact on cancer cell proliferation and cellular motility which are main attributes of metastasizing cells. Additionally, increased expression of apoptosis markers indicates that these compounds may be beneficial to regain the anti-apoptotic/pro-apoptotic balance in breast cancer cells. In vivo, both GL0385 and GL0388 show moderate tumor growth inhibition. Further chemical optimization has achieved additional drug candidates including GL0469. Breast cancer cells treated with GL0469 resulted in significant reduction of cell proliferation. Therefore, GL0385, GL0388, and GL0469 are promising new advanced lead compounds towards the development of effective therapies for breast cancers and other cancers with improved safety profiles. Further investigation is warranted to fully explore their anti-cancer potential and mechanisms of action. This project is supported by DOD Awards W81XWH-17-1-0071 and W81XWH-17-1-0072 to J.Z. and Q.S. Keywords: Bax activators, breast cancer, therapeutics, GL0385, GL0388, GL0469 Citation Format: Doerte Raphaela Fricke, Gang Liu, Hyejin Kim, Pingyuan Wang, Xi Liu, Haiying Chen, Ruixia Ma, Junhai Xu, Jia Zhou, Qiang Shen. Novel Bax activators for targeted breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3940.